Genetic Variant AMBN:c.532-1G>C (chr4-70602623-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_016519.6(AMBN):c.532-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000384 in 1,564,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AMBN
NM_016519.6 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.27

Variant links:

Genes affected

AMBN (HGNC:452): (ameloblastin) This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfect and autosomal dominant amylogenesis imperfect. [provided by RefSeq, Aug 2011]

AMBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029017856 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 7, new splice context is: atctgtgatatacctcccAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-70602623-G-C is Pathogenic according to our data. Variant chr4-70602623-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 372171.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-70602623-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6 link	c.532-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 12	ENST00000322937.10	NP_057603.1	Q9NP70-1Q546D7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10 link	c.532-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 12	1	NM_016519.6	ENSP00000313809.6		Q9NP70-1
AMBN	ENST00000449493.2 link	c.487-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 12	5		ENSP00000391234.2		Q9NP70-2

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000994

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000437

AC:

AN:

229080

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000679

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1414748

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000626

AC:

AN:

31972

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

40106

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24936

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39008

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

74798

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

51878

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1088318

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

58252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149766

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73060

show subpopulations

Gnomad4 AFR

AF:

0.0000994

AC:

0.0000994085

AN:

0.0000994085

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Amelogenesis imperfecta type 1F

Pathogenic:1

Nov 22, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.64

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.76

GERP RS

3.6

Mutation Taster

=3/97

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.70

Position offset: 8

DS_AL_spliceai

0.70

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over